This invention relates to N-[[6-methoxy-5-(trifluoromethyl)-1-naphthalenyl][substituted imino]methyl]-N-methylglycines, to the processes for their preparation, to methods for using the compounds, and to pharmaceutical preparations thereof. The compounds have pharmaceutical properties which render them beneficial for the treatment of diabetes mellitus and associated conditions.
For many years diabetes mellitus has been treated with two established types of drugs, namely insulin and oral hypoglycemic agents. These drugs have benefited hundreds of thousands of diabetics by improving their well-being and prolonging their lives. However, the resulting longevity of diabetic patients has led to complications such as neuropathy, nephropathy, retinopathy, cataracts and atherosclerosis. These complications have been linked to the undesirable accumulation of sorbitol in diabetic tissue, which in turn resulted from the high levels of glucose characteristic of the diabetic patient.
In mammals, including humans, the key enzyme involved in the conversion of hexoses to polyols (e.g. the sorbitol pathway) is aldose reductase. J. H. Kinoshita and collaborators, see J. H. Kinoshita et al, Biochem. Biophys. Acta, 158,472 (1968) and references cited therein, have demonstrated that aldose reductase plays a central role in the etiology of galactosemic cataracts by effecting the conversion of galactose to dulcitol (galactitol) and that an agent capable of inhibiting aldose reductase can prevent the detrimental accumulation of dulcitol in the lens. Furthermore, a relationship between elevated levels of glucose and an undesireable accumulation of sorbitol has been demonstrated in the lens, peripheral nervous cord and kidney of diabetic animals, see A. Pirie and R. van Heyningen, Exp. Eye Res., 3,124 (1964); L. T. Chylack and J. H. Kinoshita, Invest. Ophthal., 8,401 (1969) and J. D. Ward and R. W. R. Baker, Diabetol., 6,531 (1970).
N-Naphthoylglycine derivatives of K. Sestanj, et al, U.S. Pat. No. 4,568,693, Feb. 4, 1986, have been reported to be effective inhibitors of aldose reductase.
The present application discloses the novel N-[[6-methoxy-5-(trifluoromethyl)-1-naphthalenyl][substituted imino]methyl]-N-methylglycines represented by formula (I), which are effective inhibitors of aldose reductase. They are structurally different from the above noted aldose reductase inhibitors. The closest of the previously reported compounds is seen in U.S. Pat. No. 4,568,693 (Example 52). The present compounds differ by the replacement of a thiocarbonyl (C.dbd.S) with a substituted imine (C.dbd.N--R). Accordingly, these compounds represent an important new approach to the treatment of diabetes mellitus. The replacement of a C.dbd.S by a C.dbd.N--R in other cases is disclosed by R. Ganellin, J. Med. Chem., 24, 913, 1981; and D. E. Beattie et al, J. Med. Chem., 20, 718, 1977.